122 results about "Mesothelin" patented technology

The present invention relates to compositions and methods for treating diseases, disorders or conditions associated with dysregulated expression of mesothelin. In one embodiment, the invention relates to a fully human chimeric antigen receptor (CAR) wherein the CAR is able to target mesothelin.

This invention provides fusion proteins comprising consecutive amino acids which beginning at the amino terminus of the protein correspond to consecutive amino acids present in (i) a cytomegalovirus human MHC-restricted peptide, (ii) a first peptide linker, (iii) a human β-2 microglobulin, (iv) a second peptide linker, (v) a HLA-A2 chain of a human MHC class I molecule, (vi) a third peptide linker, (vii) a variable region from a heavy chain of a scFv fragment of an antibody, and (viii) a variable region from a light chain of such scFv fragment, wherein the consecutive amino acids which correspond to (vii) and (viii) are bound together directly by a peptide bond or by consecutive amino acids which correspond to a fourth peptide linker, wherein the antibody from which the scFv fragment is derived specifically binds to mesothelin. This invention provides nucleic acid constructs encoding same, processes for producing same, compositions, and uses thereof.

The present invention relates to compositions and methods for treating diseases, disorders or conditions associated with dysregulated expression of mesothelin. In one embodiment, the invention relates to a fully human chimeric antigen receptor (CAR) wherein the CAR is able to target mesothelin.

The invention provides a chimeric antigen receptor (CAR) (a) an antigen binding domain of HN1 or SS, a transmembrane domain, and an intracellular T cell signaling domain, or (b) an antigen binding domain of SS1, a transmembrane domain, an intracellular T cell signaling domain, and a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor 2 leader. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed.

The invention discloses a novel CAR (Chimeric Antigen Receptor) and application of novel CAR modified T cells for treating cancer. The novel CAR is formed by an extracellular signal peptide, an antigen binding structural domain, an intracellular first conduction structural domain and an intracellular second conduction structural domain, and contains an intracellular first conduction structural domain NKp44 or an intracellular first conduction structural domain TREM1. According to the novel CAR disclosed by the invention, multiple CAR nucleotide sequences are separated and purified, and the CARand CAR-T cells which specifically aims at CD19 malignant hematologic tumor and mesothelin malignant solid tumor antigens. In a hematologic tumor and solid tumor killing test, the killing capacity ofthe CAR-T cells to tumor cells is obviously enhanced, and good safety and good anti-tumor activity in clinic application are expressed.

Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

The present invention relates to a mesothelin-targeting chimeric antigen receptor and uses thereof, and specifically provides a polynucleotide sequence, which is selected from (1) a polynucleotide sequence containing the coding sequence of an anti-mesothelin single chain antibody, the coding sequence of a human CD8[alpha] hinge region, the coding sequence of a human CD8 transmembrane region, the coding sequence of a human CD28 intracellular region, the coding sequence of a human 41BB intracellular region, the coding sequence of a human CD3[zeta] intracellular region, and the coding sequence ofan optionally EGFR fragment containing an extracellular domain III and an extracellular domain IV, wherein the coding sequences are sequentially linked; and (2) the complementary sequence of the polynucleotide sequence (1). The invention further provides a related fusion protein, a vector containing the coding sequence, and uses of the fusion protein, the coding sequence and the vector.

The invention discloses a making method of relative protein mono-cloning antibody of anti-human soluble mesothelium, which is characterized by the following: predicting multi-parameter on the antigen surface position of human mesothelium B; making anti-human SMR mono-cloning antibody; making the monomer-cloning antibody (2H10 and 6D9) of relative protein; possessing higher specificity.

The present invention relates to an attenuated mutant strain of Salmonella comprising a recombinant DNA molecule encoding Mesothelin. In particular, the present invention relates to the use of said attenuated mutant strain of Salmonella in cancer immunotherapy.

Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

The invention provides an engineering immune cell with a suicide gene switch of targeting human mesothelin (MSLN). Particularly, the invention provides a chimeric antigen receptor T cell of the targeting human mesothelin, a CAR (Chimeric Antigen Receptor) structure of the cell comprises a cell suicide element, and the expression of a PD1 gene in the cell is silent. Particularly, the CAR structurecomprises a CAR basic structure and the cell suicide element at the same time, the CAR basic structure and the cell suicide element are independent of each other, and the corresponding functions of the CAR basic structure and the cell suicide element are non-interfering. In addition, the silent expression of the PD1 gene in the cell has a synergistic effect with the CAR structure, the tumor killing effect is strengthened, and the disease does not relapse easily.

Disclosed herein are MSLN binding proteins with improved binding affinities and improved ability to mediate T cell dependent killing of cancer cells expressing mesothelin. Pharmaceutical compositions comprising the binding proteins disclosed herein and methods of using such formulations are further provided.

The invention discloses an anti-human MSLN (mesothelin) monoclonal antibody, which is a specific high-affinity nano antibody developed by taking human MSLN as a target and based on a phage display technology. Compared with the prior art, the invention allows the anti-human MSLN monoclonal antibody to be successfully prepared, which is good in specificity, high in affinity and capable of binding tohuman MSLN expressed on the cell surface, and the anti-human MSLN monoclonal antibody is a potential drug for tumor immunotherapy.

The invention relates to a chimeric antigen receptor and an expression gene thereof, a double-antigen regulated type T cell modified by the chimeric antigen receptor, and application thereof. The expression gene of the chimeric antigen receptor comprises a first fusion protein expression gene and a second fusion protein expression gene, wherein the first fusion protein expression gene comprises a mucoprotein-1 antibody expression gene, a notch receptor expression gene and a Gal4-VP64 transcription activating protein expression gene which are sequentially connected; the second fusion protein expression gene comprises a Gal4-UAS promoter expression gene and an anti-mesothelin expression gene which are sequentially connected. By adopting the innovative design, the chimeric antigen receptor has the advantages that the chimeric antigen receptor can be successfully imported into the T cell to form the T cell modified by the chimeric antigen receptor; the immune reaction cannot be produced until the mucoprotein-1 and the anti-mesothelin signals simultaneously exist, so as to reach the controllable immune reaction of the chimeric antigen receptor, fewer side effects in treatment, and high specificity.

The invention discloses a Mesothelin-targeted replication-defective recombinant lentivirus CAR-T transgenic carrier which comprises a pronucleus replicon pUC Ori sequence for plasmid replication, an amicillin resistance gene AmpR containing sequence for mass amplification of target strain, virus replicon SV40Ori sequence for enhancing replication in eukaryocyte, a lentivirus packaging cis-element for lentivirus packaging, a ZsGreen1 green fluorescent protein for green fluorescence expression of eukaryocyte, an IRES ribosome combination sequence for joint transcriptional expression of protein, a human EF1(alpha) promoter for the eukaryotic transcription of chimeric antigen receptor gene, a chimeric antigen receptor for forming a second-generation CAR or third-generation CAR integrating identification, transfer and start, and an eWPRE element for improving the transgenic expression efficiency. Moreover, the invention also discloses an establishment method and application of the carrier. In the invention, the secretion of cell factors and the in-vitro killing effect of CAR-T cells can be remarkably enhanced, and the effect of clinical treatment of malignant pleural mesothelioma and pancreatic cancer is outstanding.

The invention relates to the field of tumor immunology, in particular to construction and application of chimeric antigen receptor-T (CAR-T) cells capable of targeting mesothelin and carrying a PD-L1blocking agent. The CAR-T cells are constructed by transfecting a CAR capable of targeting the mesothelin and carrying the PD-L1 blocking agent, wherein the CAR capable of targeting the mesothelin andcarrying the PD-L1 blocking agent is formed by a leader peptide of a CD8 antigen, an anti-mesothelin single-chain antibody, a hinge region, a transmembrane region, an intracellular signal domain andan anti-PD-L1 antibody secretion region which are sequentially connected with one another. The mesothelin SS1P scFv of the CAR-T cells provided by the invention can specifically bind to tumor cells expressing mesothelin glycoprotein and promote the secretion of anti-tumor-related cytokines, thereby achieving a killing effect on the tumor cells; furthermore, the CAR-T cells provided by invention can also secrete a PD-L1 antibody, specifically bind to PD-L1 produced by tumor cell expression, and block the inhibitory effect of a PD-L1 / PD-1 signal on T cell activity, thus facilitating the long-term effective inhibition of the CAR-T on tumor cell growth.

The present invention provides mesothelin peptide fragments corresponding to the CA125 binding site of mesothelin. The peptide fragments find use in disrupting the binding interaction between mesothelin and CA 125, for example, in the treatment and prevention of cancers that require the interaction of mesothelin and CA125 for growth, progression and / or metastasis.

The application relates to a mesothelin (MSLN) immunohistochemical detection kit, which contains a MSLN monoclonal antibody 3-2G6.

The invention discloses a high-affinity C-type single domain antibody of targeting mesothelin as well as a preparation method and application thereof. The high-affinity C-type single domain antibody is obtained by taking a mutant m01s of a structural domain in a human antibody IgG constant region CH2 as a skeleton, constructing a polypeptide library and then screening by taking the mesothelin as an antigen; firstly, the antibody is smaller in molecular weight, has better tissue permeability and ability to combine with antigenic epitopes with steric effects compared with a full-length single antibody, is used for treating and diagnosing some tumors (such as ovarian adenocarcinoma) with high mesothelin expression and even can be developed into an oral medicine; secondly, the plasma half lifeof the high-affinity C-type single domain antibody can reach 10 hours; finally, the high-affinity C-type single domain antibody can be expressed in a prokaryotic expression system and is low in production cost and short in period. F3 screened from the antibody has a better inhibiting effect on OVCAR-3 with high mesothelin expression and good application prospect.

Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

The invention discloses an OCTS technology-based pancreatic cancer and malignant mesothelioma CAR-T therapy vector. The vector comprises lentivirus framework plasmid, a human EF1alpha promoter (SEQ ID NO. 14), an OCTS chimeric receptor structural domain and a PDL1 single-chain antibody; the OCTS chimeric receptor structural domain comprises CD8 leader chimeric receptor signal peptide (SEQ ID NO. 15), a PDL1 single-chain antibody light chain VL (SEQ ID NO. 16), a PDL1 single-chain antibody heavy chain VH (SEQ ID NO. 17), an MESOTHELIN single-chain antibody light chain VL (SEQ ID NO. 18), an MESOTHELIN single-chain antibody heavy chain VH (SEQ ID NO. 19), an antibody inner linker Inner-Linker (SEQ ID NO. 20), a single-chain antibody inter-linker Inter-Linker (SEQ ID NO. 21), a CD8 Hinge chimeric receptor linker (SEQ ID NO. 22), a CD8Transmembrane chimeric receptor transmembrane domain (SEQ ID NO. 23), a TCR chimeric receptor T-cell activation domain (SEQ ID NO. 26), and a chimeric receptor inducible co-stimulater area. In addition, the invention also discloses a construction method of the vector as well as application of the vector to preparation of medicines for treating pancreatic cancer and malignant mesothelioma.

In one embodiment, methods are provided for assessing the presence of mesothelin-expressing tumor cells in a human subject. In another embodiment, methods are provided for monitoring the efficacy of treatment of a human cancer patient diagnosed with a mesothelin-expressing tumor.

The invention provides a human mesothelin chimeric antigen receptor and a T cell, a preparation method and use thereof. The mesothelin chimeric antigen receptor comprises an anti-mesothelin scFv antibody, a CD8 hinge region, a CD28 transmembrane region, a CD3 intracellular region and a 41BB intracellular region. Nucleic acid encoding the receptor, a vector containing the nucleic acid and a host cell comprising the vector are further provided. A method for using the vector for transducing human CD8+ / CD4+ T cells to obtain the CARmesothelin-T cell is further provided. The cell is obtained by genetic modification of the T cell and can be used for treating diseases related to mesothelin expression, especially for specifically recognizing and killing mesothelin expression tumors.

The invention discloses a chimeric antigen receptor mMesothelin scFv-CD8H&M-CD28-41BB-CD 3zeta-mbIL15 and use thereof. The chimeric antigen receptor is formed by series connection of a light chain andheavy chain variable region (MesothelinscFv) of an anti-mouse Mesothelin monoclonal antibody (with a cloning number being SS1), a human CD8alpha hinge region, a human CD8 transmembrane region, a human CD28 and 41 BB intracellular region, a human CD3zeta intracellular region and an IL15+IL15Ralphla structure. The Meso-mbIl15 CART cell prepared by the invention has a strong killing function on specific tumor cells; and the prepared Meso-mbIl15 CART cell has very good multiplication capacity.